Inhibitors of glutaminyl cyclase

Abstract

Compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: A represents and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z are as defined throughout the description and the claims.

1. A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein: 
         R 1  represents alkyl; alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; —C 1-6 alkyl-carbocyclyl; heterocyclyl; —C 1-6 alkyl-heterocyclyl; aryl; heteroaryl; —C 1-6 alkylaryl; —C 1-6 alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused to heterocyclyl; 
         in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; 
         and in which any of the aforesaid phenyl, aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)OC 1-6 alkyl, —SOC 1-4 alkyl and —SOC 3-6 cycloalkyl; 
         or R 1  represents phenyl substituted by phenyl, or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C 1-4 alkyl, halogen and C 1-4 alkoxy; 
         or R 1  represents phenyl substituted by benzyloxy- in which any of the aforesaid phenyl or benzyloxy groups may optionally be substituted on the ring by one or more groups selected from C 1-4 alkyl, halogen and C 1-4 alkoxy; 
         X represents C or N; 
         and 
         A represents 
       
       
         
           
           
               
               
           
         
         wherein Y represents a C 2-5  alkylene chain, which may optionally be substituted by one or two methyl groups or may optionally be substituted by two alkylene substituents at the same position wherein the two alkylene substituents are joined to each other to form a C 3-5 spiro-cycloalkyl group and 
         R 2 , R 3  and R 4  independently represent H or C 1-2 alkyl, provided that R 2  and R 3  and R 4  do not all represent H; or 
         A represents 
       
       
         
           
           
               
               
           
         
         wherein Z represents a bond, —CH 2 —, —CH 2 —CH 2 —, —CH(Me)—, —CH(Me)—CH 2 — or —CH 2 —CH(Me)— and 
         R 5  and R 6  independently represent H or C 1-2 alkyl 
         and 
         B represents H or methyl. 
       
     
     
       2. A compound according to  claim 1  wherein R 1  represents alkyl;
 alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; —C 1-6 alkyl-carbocyclyl; heterocyclyl; —C 1-6 alkyl-heterocyclyl; aryl; heteroaryl; —C 1-6 alkylaryl; —C 1-6 alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused to heterocyclyl; 
 in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; 
 and in which any of the aforesaid phenyl, aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2  and —C(O)NH(C 1-4 alkyl); 
 or R 1  represents phenyl substituted by phenyl, or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C 1-4 alkyl, halogen and C 1-4 alkoxy. 
 
     
     
       3. A compound according to  claim 1  wherein R 1  represents aryl; heteroaryl; -phenyl fused to carbocyclyl; phenyl fused to heterocyclyl;
 or R 1  represents phenyl substituted by phenyl, or phenyl substituted by a monocyclic heteroaryl group; in which any of aforementioned aryl, phenyl, heteroaryl, carbocyclyl and heterocyclyl may optionally be substituted. 
 
     
     
       4. A compound according to  claim 1  wherein R 1  represents optionally substituted aryl. 
     
     
       5. A compound according to  claim 4  wherein R 1  is phenyl substituted by one, two or three substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen and cyano. 
     
     
       6. A compound according to  claim 4  wherein R 1  represents unsubstituted aryl selected from phenyl, naphthalen-1-yl and naphthalen-2-yl. 
     
     
       7. A compound according to  claim 3  wherein R 1  represents optionally substituted phenyl fused to optionally substituted heterocyclyl. 
     
     
       8. A compound according to  claim 3  wherein R 1  represents optionally substituted heteroaryl. 
     
     
       9. A compound according to  claim 1  wherein A represents 
       
         
           
           
               
               
           
         
         wherein Y, R 3  and R 4  are as defined in  claim 1 . 
       
     
     
       10. A compound according to  claim 9  wherein
 R 2  represents H, 
 R 3  represents H and 
 R 4  represents methyl. 
 
     
     
       11. A compound according to  claim 9  wherein Y represents an unsubstituted C 2-5  alkylene chain. 
     
     
       12. A compound according to  claim 11  wherein Y represents —(CH 2 ) 3 — or —(CH 2 ) 4 —. 
     
     
       13. A compound according to  claim 12  wherein A represents 
       
         
           
           
               
               
           
         
       
     
     
       14. A compound according to  claim 1  wherein A represents 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6  and Z are as defined in  claim 1 . 
       
     
     
       15. A compound according to  claim 14  wherein
 R 5  represents H and 
 R 6  represents H. 
 
     
     
       16. A compound according to  claim 14  wherein
 Z represents a bond, —CH 2 — or —CH 2 —CH 2 —. 
 
     
     
       17. A compound according to  claim 1  wherein B represents H. 
     
     
       18. A compound according to  claim 1  as defined in any one of examples 1 to 30:
 (1) 2-cyano(4-ethylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (2) 2-cyano(4-isopropylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (3) 2-cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (4) 2-cyano(4-cyanophenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (5) 2-cyano(3,4,5-trimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (6) 2-cyano(4-ethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (7) 2-cyano(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(3,4-dimethylphenyl)guanidine, 
 (8) (3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-mesitylguanidine, 
 (9) (3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(biphenyl-4-yl)guanidine, 
 (10) (3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-2-yl)guanidine, 
 (11) (3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-1-yl)guanidine, 
 (12) (3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(benzo[c][1,2,5]thiadiazol-6-yl)-2-cyanoguanidine, 
 (13) (3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(3,4-dichlorophenyl)-2-cyanoguanidine, 
 (14) (benzo[d][1,3]dioxol-6-yl)-2-cyano-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (15) 2-cyano(4-methoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (16) 2-cyano(3,5-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine, 
 (17) 2-cyano(4-ethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (18) 2-cyano(3,5-dimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (19) 2-cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (20) 2-cyano(mesityl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (21) 2-cyano(4-isopropylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (22) 2-cyano(4-ethylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (23) 2-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-1-yl)guanidine 
 (24) (benzo[c][1,2,5]thiadiazol-6-yl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (25) 2-cyano(3,4,5-trimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (26) 2-cyano(4-cyanophenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (27) (3,4-dichlorophenyl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (28) 2-cyano(4-methoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine 
 (29) 2-cyano-1-[3-(4-methyl-1H-imidazol-1-yl)propyl]-4-phenylbenzene-1-guanidine 
 (30) 2-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-2-yl)guanidine 
 or a pharmaceutically acceptable salt, solvate or polymorph of any one thereof. 
 
     
     
       19. A pharmaceutical composition comprising a compound according to  claim 1  optionally in combination with one or more therapeutically acceptable diluents or carriers. 
     
     
       20. The pharmaceutical composition of  claim 19 , which comprises additionally at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs. 
     
     
       21. The pharmaceutical composition of  claim 19  which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS. 
     
     
       22. A process for preparation of a compound of formula (I) according to  claim 1 , which comprises reaction of a compound of formula (II) 
       
         
           
           
               
               
           
         
         with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , A and B are as defined in  claim 1 . 
       
     
     
       23. A process for preparation of a compound of formula (I) according to  claim 1 , which comprises reaction of a compound of formula (VI) 
       
         
           
           
               
               
           
         
         wherein R 7  represents C 1-6 alkyl and R 1  is as defined in  claim 1 ; 
         and X represents C or N; 
         with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein A and B are as defined in  claim 1 . 
       
     
     
       24. The pharmaceutical composition of  claim 19  which comprises additionally at least one compound, selected from the group consisting of PEPinhibitors, LiCI, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.